rs1057518646

Variant names:

• chr12-7088721-GCACTTGATGA-TGTCC
• rs1057518646
• NM_001733.7:c.917_927delTCATCAAGTGCinsGGACA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The NM_001733.7(C1R):​c.917_927delTCATCAAGTGCinsGGACA​(p.Ile306_Cys309delinsArgThr) variant causes a missense, disruptive inframe deletion, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense, disruptive_inframe_deletion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.42
• Publications: 1 publications found

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

C1R Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, periodontal type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• autosomal systemic lupus erythematosus type 16

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001733.7.
• PP5: Variant 12-7088721-GCACTTGATGA-TGTCC is Pathogenic according to our data. Variant chr12-7088721-GCACTTGATGA-TGTCC is described in ClinVar as Pathogenic. ClinVar VariationId is 267355.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	NM_001733.7	MANE Select	c.917_927delTCATCAAGTGCinsGGACA	p.Ile306_Cys309delinsArgThr	missense disruptive_inframe_deletion splice_region	N/A	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.959_969delTCATCAAGTGCinsGGACA	p.Ile320_Cys323delinsArgThr	missense disruptive_inframe_deletion splice_region	N/A	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.917_927delTCATCAAGTGCinsGGACA	p.Ile306_Cys309delinsArgThr	missense disruptive_inframe_deletion splice_region	N/A	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.1070_1080delTCATCAAGTGCinsGGACA	p.Ile357_Cys360delinsArgThr	missense disruptive_inframe_deletion splice_region	N/A	ENSP00000573910.1
	C1R	ENST00000903850.1		c.989_999delTCATCAAGTGCinsGGACA	p.Ile330_Cys333delinsArgThr	missense disruptive_inframe_deletion splice_region	N/A	ENSP00000573909.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Ehlers-Danlos syndrome, periodontal type 1 (2)
1	-	-	Ehlers-Danlos syndrome, periodontal type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057518646;

hg19: chr12-7241317;